UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombomodulin plays a role as a cofactor for thrombin-catalyzed activation of protein C on endothelial cells. We examined the effect of homocysteine, a stimulant of atherosclerosis and thrombotic disease, on the cofactor activity and protein level of thrombomodulin and also on the expression of thrombomodulin in endothelial cells. Homocysteine inhibited the cofactor activity of thrombomodulin both on the surface of endothelial cells and in the whole cells dose- and time-dependently, and maximal inhibition of the cofactor activity occurred after a 3- to 6-hour incubation with 10 mmol/L homocysteine (10% of initial activity). Homocysteine also decreased the amount of intact (unreduced) thrombomodulin in endothelial cells. However, at the same condition the total protein level (reduced and unreduced form) of thrombomodulin, determined by dot immunoblot analysis using the monoclonal antibody that recognized both reduced and unreduced thrombomodulin, decreased slightly, and the mRNA level of thrombomodulin showed a twofold to three-fold increase. After 24 hours of incubation, the cofactor activity and total protein level of thrombomodulin were 60% and 165% of the initial values, respectively. When purified thrombomodulin fixed to a microwell plate was treated with homocysteine, both cofactor activity and thrombin-binding ability to the thrombomodulin were decreased in proportion to the concentration of homocysteine. These findings suggest that homocysteine directly inhibited the cofactor activity of thrombomodulin on endothelial cells by reducing the disulfide-bond rich epidermal growth factor-like structures of thrombomodulin. This would a result in the decrease of the antithrombotic property of endothelium and may also trigger off the synthesis of mRNA and protein of thrombomodulin to maintain the antithrombotic properties of the cells.
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PMID:An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. 131 88

A patient with an 18 year history of recurrent arterial thrombosis and no evidence of atherosclerosis or embolism of cardiac origin presented with a prolonged thrombin clotting time when performed with human thrombin. The bovine thrombin clotting time was only slightly prolonged. During 30 months of follow-up, the thrombin time fluctuated, but remained prolonged. The patient has been treated with an oral anticoagulant for the past 8 years, with no thrombotic recurrence. The inhibitor activity was due to the presence of polyclonal IgGs which bound to thrombin-Sepharose. The influence of IgGs purified from the patient's serum was compared to the influence of normal IgGs in several systems exploring the catalytic activity of thrombin and the binding of the enzyme to macromolecular substrates through secondary binding site(s). We found that the IgGs did not impair the catalytic activity toward small synthetic substrates, but inhibited the binding of thrombin to fibrinogen, thrombomodulin and heparin cofactor II. Such proteins are known to require a secondary binding site of thrombin to interact with the enzyme. The anti-thrombin antibody might have resulted from an abnormal generation of thrombin. This would be the consequence of the process favouring thrombosis. Alternatively, the autoantibody might have favoured thrombosis primarily, by impairing natural antithrombotic mechanisms triggered by thrombin.
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PMID:Partial characterization of an autoantibody recognizing the secondary binding site(s) of thrombin in a patient with recurrent spontaneous arterial thrombosis. 132 Mar

Thrombin is a multifunctional serine protease generated at sites of vascular injury. A host of thrombin actions on vascular endothelial cells, smooth muscle cells, and macrophages has been defined in cell culture systems, but the in vivo significance of these activities is unknown. We have defined the expression of the recently identified receptor for thrombin in human arteries by both in situ hybridization and immunohistochemistry. In normal-appearing arteries, thrombin receptor was expressed almost exclusively in the endothelial layer. By contrast, in human atheroma, the receptor was widely expressed, both in regions rich in macrophages and in regions rich in vascular smooth muscle cells and mesenchymal-appearing intimal cells of unknown origin. Thrombin receptor was expressed by human vascular endothelial cells and smooth muscle cells in culture and by macrophages obtained by bronchioalveolar lavage, thus demonstrating that all three cell types are indeed capable of expressing the thrombin receptor. These results establish thrombin receptor activation as a candidate for contributing to sclerotic and inflammatory processes in the human vasculature, such as those that occur in atherosclerosis and restenosis.
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PMID:Thrombin receptor expression in normal and atherosclerotic human arteries. 132 4

Several pieces of evidence suggest that vascular endothelium may be a site of latent herpetic viral infection, and that activation of such infection might cause or aggravate atherosclerosis. The present studies which utilized HSV-1 infection of cultured endothelial monolayers, provide insights into two phenomena seemingly relevant in considerations of atherosclerosis. Thus, mechanisms are reported by which infected endothelium may be damaged by marginated inflammatory cells, and be transformed from an anticoagulant to a procoagulant tissue. First, granulocytes are attracted to, and avidly bind, endothelium infected for very brief periods. This interaction is associated with denudation of intact cells as well as actual cytolysis through release of PMN proteases and toxic oxygen species. Second, several potentially additive abnormalities of HSV-infected endothelium would seem to foster coagulation. These include: a) its loss of surface heparans and thrombomodulin; b) its inability to synthesize prostacyclin with associated incapacity to deter platelet adhesion; c) its disordered membrane lipid conformation which is likely associated with excessive surface thrombin generation; and d) its unique ability to generate and release tissue factor. We speculate that mechanical abrasion may reactivate latent herpes (HSV or CMV) infection in endothelial cells particularly those exposed to high shear forces--for instance, at vessel bifurcations. This may underlie the endothelial damage, clotting and atheroma formation commonly found at these sites.
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PMID:Herpes virus infection of endothelium: new insights into atherosclerosis. 132 3

We have previously demonstrated that human aortic endothelium exhibits morphologic heterogeneity in situ, and this heterogeneity can be reproduced in culture. In this study, we have compared prothrombotic properties of cultured endothelial cells (EC) from areas of human aorta at high risk for atherosclerosis (HP-EC) with EC from areas at low risk (LP-EC). Using paired cultures from the same donors, we have found that the expression of cell surface thrombomodulin (TM)--as measured by the ability to generate activated protein C (APC) from protein C in the presence of thrombin--is relatively reduced on HP-EC compared to LP-EC (respectively, 4.98 +/- 4.43 vs. 5.83 +/- 4.37 pM APC/min/cm2; p = .03, n = 12). Furthermore, HP-EC more efficiently assemble the prothrombinase complex on their cellular surface, resulting in an increased rate of thrombin generation from prothrombin (9.81 +/- 3.10 (HP-EC) vs. 7.96 +/- 3.20 nM thrombin/min/cm2 (LP-EC); p less than .03, n = 7). The combination of reduced TM expression and increased prothrombinase complex assembly on HP-EC suggests a prothrombotic phenotype in these cells. These findings may be important in the pathogenesis of thrombosis associated with atherosclerotic plaques.
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PMID:Prothrombotic phenotype diversity of human aortic endothelial cells in culture. 133 14

Endothelial cells produce the 21-amino acid peptide endothelin, which is formed from its precursor, big endothelin, via the activity of converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and hypoxia. In vascular smooth muscle, endothelin binds to a specific receptor (ETA-subtype), which activates phospholipase C, leads to the formation of inositol trisphosphate, diacylglycerol (which activates protein kinase C), and increased intracellular Ca2+. In certain blood vessels, the endothelin receptor on vascular smooth muscle is linked to a voltage-operated Ca2+ channel via a G-protein. This explains why Ca2+ antagonists inhibit endothelin-induced contractions in certain, but not all, blood vessels. In the human forearm circulation, Ca2+ antagonists do prevent endothelin-induced contractions and unmask endothelin-induced vasodilation mediated by endothelial prostacyclin production (via the ETB-receptor). The pulmonary circulation plays an important role in the metabolism of endothelin, as the lungs take up large quantities of the peptide during passage. Endothelin has profound vasoconstrictor effects in the pulmonary circulation (and also in bronchial tissue), and its production is augmented in pulmonary hypertension. In systemic hypertension, the circulating endothelin levels appear to be normal. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are increased. Thus, endothelin is a potent mediator in the systemic and pulmonary circulation and, in particular, in diseases of the vasculature.
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PMID:Endothelin: systemic arterial and pulmonary effects of a new peptide with potent biologic properties. 133 60

We investigated whether biologically relevant concentrations of the mono-hydroxyeicosatetraenoic acids (mono-HETEs) modulate platelet functions. We report that 15-HETE, an eicosanoid produced by endothelial cells, granulocytes, and lymphocytes, potentiated platelet aggregation, nucleotide release, and elevation in intracellular calcium levels induced by a threshold concentration of thrombin (0.025 U/mL). Significant potentiation effects on these responses were observed at concentrations between 1 and 100 nmol/L. 15-HETE at these concentrations enhanced thrombin-induced platelet aggregation by 32% to 57%, nucleotide release by 40% to 65%, and elevation of intracellular calcium by 31% to 52% (P < .05 to .01). Both 12-HETE and 5-HETE, the structural isomers of 15-HETE, also potentiated thrombin-induced platelet aggregation and nucleotide release. While 12-HETE showed a small but significant effect at 100 pmol/L, 5-HETE had effects similar to those of 15-HETE at micromolar concentrations. To understand the mechanism of the HETE modulation of platelet functions, we studied the effect of 10 and 100 nmol/L 15-HETE on the production of sn-1,2-diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (1,4,5-IP3). 15-HETE enhanced thrombin-induced production of DAG and 1,4,5-IP3 in a time- and concentration-dependent manner. 15-HETE also potentiated agonist-induced phosphorylation of the 47-Kd platelet protein. These studies demonstrate an important modulatory role for 15-HETE on platelet functions. Since this eicosanoid is elevated in pathologic states associated with platelet hyperfunction, including diabetes mellitus and atherosclerosis, an elucidation of its mechanism(s) of action appears relevant to our understanding of the genesis of atherothrombotic vascular disease.
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PMID:15-Hydroxyeicosatetraenoic acid-mediated potentiation of thrombin-induced platelet functions occurs via enhanced production of phosphoinositide-derived second messengers--sn-1,2-diacylglycerol and inositol-1,4,5-trisphosphate. 133 1

Injury to the vascular endothelium and the subsequent inflammatory response are considered prerequisites for the development of atherosclerosis. Platelet-derived growth factor (PDGF) production by and monocyte adhesion to aortic endothelial cells (EC) may participate in this inflammatory process and therefore are two potential targets for control by anti-inflammatory agents. Our previous studies have demonstrated that monocyte adhesion and PDGF production are stimulated by thrombin in EC. Here, we provide evidence that treatment of EC with the anti-inflammatory agent 3-deazaadenosine (c3Ado) effectively abolished thrombin-stimulated PDGF production and monocyte adhesion. c3Ado had no significant effect on either basal monocyte adhesion or constitutive PDGF production. c3Ado was also effective in negating monocyte adhesion induced by other agonists, such as interleukin-1, phorbol 12-myristate 13-acetate (PMA), and lipopolysaccharide. Northern analysis demonstrated that c3Ado significantly reduced thrombin- and PMA-stimulated steady-state levels of PDGF-A chain, PDGF-B chain, and endothelial-leukocyte adhesion molecule-1 (ELAM-1) mRNAs. Nuclear run-on studies demonstrated that a marked transcriptional activation of these genes by thrombin and PMA was abrogated by c3Ado treatment. The transcriptional rate of the alpha-tubulin gene was unaffected by the drug. Antibody binding studies with an anti-ELAM-1 monoclonal antibody 7A9 revealed that thrombin-stimulated EC expression of ELAM-1 was abolished by c3Ado, indicating that the suppression of ELAM-1 expression on EC surface may be a mechanism by which c3Ado interferes with monocyte adhesion. Experiments with the nucleoside transport inhibitor nitrobenzylthioinosine suggested that the transport of c3Ado into EC was required for its inhibitory activity. In addition, L-homocysteine thiolactone was found to potentiate the inhibitory activity of c3Ado, suggesting that the accumulation of intracellular c3Ado homocysteine may be the underlying mechanism by which c3Ado inhibits thrombin-induced EC function. Taken together, these results indicate that c3Ado may prove effective against vascular injury and inflammation through its ability to inhibit induction of both monocyte adhesion and PDGF production.
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PMID:3-Deazaadenosine inhibits thrombin-stimulated platelet-derived growth factor production and endothelial-leukocyte adhesion molecule-1-mediated monocytic cell adhesion in human aortic endothelial cells. 137 93

Rabbit plasma low density lipoprotein (LDL) contains one major apolipoprotein of apparent molecular weight of 320 kDa, designated apolipoprotein (apo) Bh, while another component termed apoB1 of apparent molecular weight of 220 kDa is found in chylomicrons. The fragments generated by thrombin digestion of the protein moieties of rabbit and human LDL were separated by polyacrylamide gradient gel electrophoresis and compared. As in the human species, the enzyme produced limited cleavage patterns of rabbit LDL apoB. Within the first 2 h, two fragments (Tr1 and Tr2, with apparent molecular weights 280,000 and 44,000, respectively) appeared. Longer incubations led to the production of two additional peptides, Tr3 and Tr4 (apparent molecular weights 180,000 and 96,000, respectively). Ten monoclonal antibodies, developed against rabbit LDL and designated P01 to P10, were found to react with rabbit apoB. Some also cross-reacted with human apoB. Epitope mapping, performed with these antibodies, showed that Tr3 and Tr4 were derived from the further degradation of Tr1. The rabbit is one of the most frequently used animals in atherosclerosis research. Its LDL receptor has been characterized and there exists a strain of homozygous LDL receptor-deficient rabbits referred to as WHHL rabbits. Despite this, little has been done to characterize the structure of rabbit apoB; only a short region has been sequenced and shown to be the carboxyl-terminal region, the rabbit apoB1. The molecular weight of human apoB (550,000) is much larger than rabbit apoBh. In both species, a primary and secondary thrombin cleavage occur, but the size of the fragments produced is very different between the two species. Identification of the thrombolytic fragments of the rabbit apoB have afforded the opportunity to compare the structures of both apoB species.
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PMID:Thrombin cleavage of apolipoprotein Bh of rabbit LDL: structural comparisons with human apolipoprotein B-100. 138 Sep 72

We investigated heparin cofactor II (HC II) levels and their relationship to other haemostatic factors in the elderly in comparison with antithrombin III (AT III). We measured plasma HC II activity levels in 166 subjects aged from 61 to 99 years using a chromogenic method. HC II levels (94.4 +/- 18.5%) in the healthy elderly subjects were significantly (p less than 0.001) lower than in 40 healthy adult controls under 60 years of age (mean age: 51.5 years; 111.6 +/- 21.2%). HC II levels in the elderly subjects decreased further with age (r = 0.308, p less than 0.001) and the extent of the decrease was more marked than that for AT III (r = 0.179, p less than 0.05). There was no significant sex difference in HC II levels in the elderly. HC II levels correlated significantly with AT III levels and with acute phase reactants including sialic acid, fibrinogen, and PAI-1. HC II levels also correlated with factor VII, plasminogen, alpha 2-plasmin inhibitor, serum lipid, pseudocholinesterase, and albumin levels. These correlations were also found for AT III except active PAI-1 and tPA-PAI-1 complexes, but the correlations with acute phase reactants were stronger for HC II than AT III. We divided 154 elderly subjects into 4 groups by their pseudocholinesterase and albumin levels to estimate the effect of nutritional status on antithrombin activity in the elderly. HC II levels were normal in the elderly subjects with a good nutritional state (103 +/- 18%), but were significantly decreased in those with malnutrition (85 +/- 15%, p less than 0.001). AT III levels also showed the same tendency. These results indicate a decrease in the reserve capacity to inhibit thrombin generation at sites of atherosclerosis in response to trigger events. The deficiency of two major antithrombin factors in the elderly may indicate a tendency to thrombosis, especially in individuals with malnutrition. When considering the clinical significance of HC II, several other parameters, including age, nutritional status, hepatic synthetic ability, and the presence or absence of acute phase reaction should also be assessed.
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PMID:Heparin cofactor II deficiency in the elderly: comparison with antithrombin III. 138 49

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